Hyperprogression upon cemiplimab alone or with chemotherapy in PD-L1 ≥ 50% NSCLC: a biomarker guided phase 2 trial – HYPERBOLIC study

Prior treatment

• Any infection requiring hospitalization or treatment with IV anti-infectives within 2 weeks of first dose of study medication 2. Known uncontrolled infection with HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent). No serological testing is required unless mandated by local health authority. 3. Administration of live or live-attenuated vaccines within 30 days before the baseline LDNs assessment. Administration of killed vaccines is allowed. Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication. 4. History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management. 5. Administration of radiotherapy within 7 days prior to the baseline LDNs assessment. 6. Administration of colony-stimulating factors (e.g., G-CSF, GM-CSF) or recombinant erythropoietin within 28 days prior to the baseline LDNs assessment. Primary prophylaxis with G-CSF and pegylated G-CSF is not allowed. Secondary prophylaxis is not recommended and required case-by-case discussion with the coordinator center before G-CSF administration. 7. Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment. 8. Female patients who are pregnant, breast-feeding, male, or female patients of reproductive potential who are not employing an highly effective method of birth control. 9. Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results. 10. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment (Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable). 11. Allogenic tissue/solid organ transplant.
• Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Allogenic tissue/solid organ transplant.
• Administration of live or live-attenuated vaccines within 30 days before the baseline LDNs assessment. Administration of killed vaccines is allowed. Receipt of COVID-19 vaccination within 1 week of planned start of study medication or for which the planned COVID-19 vaccinations would not be completed 1 week prior to start of study medication.
• Administration of palliative radiotherapy within 7 days prior to the baseline LDNs assessment.
• Patients with a condition requiring chronic corticosteroid therapy (>10 mg of prednisone per day or equivalent) within 7 days prior to the start of prescreening procedures. Patients receiving a short course of steroid therapy for clinical reasons are not excluded, but a case-by-case discussion with the Coordinating Center will be required.
• Administration of colony-stimulating factors (e.g., G-CSF, GM-CSF) or recombinant erythropoietin within 28 days prior to the baseline LDNs assessment.
• Ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. a. The following are not exclusionary: vitiligo, childhood asthma that has resolved, endocrinopathies (such as hypothyroidism or type 1 diabetes) that require only hormone replacement, or psoriasis that does not require systemic treatment.

Other illness

• Any condition that, in the opinion of the investigator, would interfere with the evaluation of the study drug or interpretation of patient safety or study results
• Known uncontrolled infection with HIV, hepatitis B or hepatitis C infection, diagnosis of immunodeficiency, and/or tuberculosis (active or latent). No serological testing is required unless mandated by the local health authority.
• History of interstitial lung disease (eg, idiopathic pulmonary fibrosis or organizing pneumonia), of active, or noninfectious pneumonitis that required immune-suppressive doses of glucocorticoids to assist with management.

Lab values

• Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).

Other

• Female patients who are pregnant or breast-feeding. Male or female patients of reproductive potential who are not employing a highly effective method of birth control.

• The participant (or legally acceptable representative) has provided documented informed consent to participation to the study and data protection consent form.
• Adequate organ and marrow function as defined below: ⮚ Absolute neutrophil count > 1.5 x 109/L ⮚ Platelets ≥ 100,000/mm3 ⮚ Haemoglobin ≥ 9.0 g/dL ⮚ Estimated glomerular filtration rate (according to CDK-EPI equation): ≥ 60ml/min/1.73 m2 for patients receiving cisplatin; ≥30 ml/min/1.73 m2 for patients receiving carboplatin; Estimated glomerular filtration rate (according to Cockgroft-Gault equation): ≥45 ml/min/1.73 m2 for patients receiving pemetrexed ⮚ Total bilirubin ≤1.5 × upper limit of normal (ULN) (if liver metastases ≤3 × ULN), with the exception of patients diagnosed with clinically confirmed Gilbert’s syndrome ⮚ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN or ≤5 × ULN, if liver metastases at baseline.
• Absence of a known severe hypersensitivity (≥ Grade 3) to any of the study chemotherapy agents and/or cemiplimab and/or to any of their excipients.
• Male or female aged 18 years or older.
• ECOG Performance Status of 0 – 2.
• Pathologically (histologically or cytologically) confirmed diagnosis of stage IV NSCLC (TNM 8th edition), who received no prior systemic treatment for recurrent or metastatic NSCLC. Mixed squamous/non-squamous tumors are eligible.
• PD-L1 TPS ≥ 50% (by local test).
• Absence of the following targetable oncogene alterations: EGFR, ALK, ROS1, and RET.
• Circulating CD10- LDNs >30.5% at baseline. LDNs will be defined as CD11b+CD15+CD10- cells among live peripheral blood mononuclear cells (PBMCs) analyzed by flow cytometry at baseline during the pre-screening phase. Raw flow cytometry data collected at the Hub center laboratory will be centrally analyzed by the Coordinating Center.
• Measurable disease (according to RECIST v.1.1) on two sequential CT scans performed before randomization. The following criteria must be fulfilled: ⮚ Participants must have at least one measurable lesion that has not been previously treated with radiotherapy; ⮚ Chest and abdomen CT scan are mandatory; ⮚ Availability of measurable disease imaging, to be anonymized and uploaded via the trial-specific cloud platform for central independent confirmation by a radiologist at the coordinating center. ⮚ A minimum 2-week interval and a maximum 12-week interval will be acceptable between the two pre-treatment CT scans. ⮚ The baseline scan will have to be performed within a maximum 4-week interval before treatment start.
• Patient’s willingness to undergo blood draws and tumor tissue collection (including re-biopsy procedures, when applicable) for analysis according to study objectives.